Bispecific Antibody Demonstrates Antitumor Activity in Heavily Pretreated NHL

Article

Treatment with REGN1979, a human anti-CD20 &times; anti-CD3 bispecific IgG4 antibody, showed high clinical activity and tolerability in heavily pretreated patients with relapsed/refractory B-cell non-Hodgkin lymphoma.<br /> &nbsp;

Rajat Bannerji, MD, PhD

Rajat Bannerji, MD, PhD

Rajat Bannerji, MD, PhD

Treatment with REGN1979, a human anti-CD20 &times; anti-CD3 bispecific IgG4 antibody, showed high clinical activity and tolerability in heavily pretreated patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL).

Results from a phase I study presented at the 61st American Society of Hematology Annual Meeting and Exposition demonstrated an overall response rate (ORR) of 95.5% and a complete response (CR) rate of 77.3% among 22 patients in the study with R/R follicular lymphoma (FL) who were treated with &ge;5 mg of REGN1979. Patients with R/R FL who were treated with &ge;80 mg of REGN1979 had an ORR of 100%, according to Rajat Bannerji, MD, PhD, chief of hematologic malignancies at the Rutgers Cancer Institute of New Jersey, New Brunswick, who presented the findings.

In the R/R FL cohort, the median progression-free survival was 11.4 months (95% CI, 6.7-not evaluable). At data cutoff (September 3, 2019), 14 of 21 responses were ongoing, and 12 of 17 patients who had achieved a CR had ongoing CRs at the last tumor assessment. Median duration of follow-up in this group was 6.8 months.

In the subset of patients with R/R diffuse large B-cell lymphoma (DLBCL), dose-related responses were observed. With treatment at &ge;80 mg of REGN1979, the ORR rate was 57.9% and the CR rate was 42.1%. At this dosage, the ORR was 71.4% in those patients not treated with prior chimeric antigen receptor (CAR) T-cell therapy (n = 7), which included all CRs. In those who received prior CAR T-cell therapy, the ORR and CR rate were 50% and 25%, respectively. The responses appear durable, said Bannerji, as all CRs were ongoing at the last tumor assessment.

&ldquo;Using this step-up dosing strategy, we were able to go to the maximum planned dose of the protocol without any dose-limiting toxicity,&rdquo; he said.

At a median follow-up of 5.3 months, all 5 patients with R/R DLBCL without prior CAR T-cell therapy who responded to &ge;80 mg of REGN1979 had ongoing responses at the last tumor assessment. In this subset of patients with R/R DLBCL who also had prior CAR T-cell therapy, the median follow-up was 2.6 months. Four out of 6 patients who responded had an ongoing response at the last tumor assessment, and all 3 with CRs maintained their CR at last tumor assessment.

In both of the above subsets of B-cell malignancies, baseline CD20 level did not predict response or nonresponse, but some progression may be associated with loss of CD20, said Bannerji. PD-L1 expression and PD-1—positive tumor infiltrating lymphocytes in malignant lymph node tissue increased following REGN1979 treatment. &ldquo;This suggests that these bispecific [antibodies] may have some synergy with checkpoint inhibitors,&rdquo; he said.

ORR and CR rates were 67% and 33% each, respectively, for enrolled patients with mantle cell lymphoma (MCL; n = 6) or marginal zone lymphoma (MZL; n = 6).

Eligible patients were those with R/R B-cell NHL who received prior CD20-directed therapy. Per study protocol, REGN1979 was administered over a 36-week period. Patients first received 12 weekly doses delivered intravenously followed by an every-2-week administration for a total of 12 doses.

A total of 110 patients were entered: 61 with DLBCL; 31 with grade 1 to 3a FL; 9 with MCL; 6 with MZL; and 3 with other B-cell malignancies, which could have included grade 3b FL or Waldenstr&ouml;m macroglobulinemia. The median number of prior lines of therapy was 3. Eighty percent of patients were refractory to their most recent prior line of therapy and 15.5% had relapsed (data were missing for the other 4.5%).

At the analysis, 31 patients (28.2%) were continuing on the study; 10 (9.1%) had completed the study. Of the 69 patients who discontinued the study, 35 did so for progression or disease recurrence, 6 were due to physician decision, 5 were due to patient decision, 1 was because of an adverse event (AEs), 9 were for other reasons, and 13 had died.

The most common treatment-emergent AEs observed in all patients were pyrexia (80%), cytokine release syndrome (CRS; 59.1%), and chills (50.9%). The most common grade 3/4 AEs were anemia (21.8%), hypophosphatemia (19.1 %), lymphopenia (19.1 %), and neutropenia (19.1 %).

&ldquo;Infusion-related reactions (IRRs) and CRS events occurred predominantly during weeks 1 through 3 and declined thereafter, without a dose-dependent increase in incidence or severity,&rdquo; Bannerji said. No patient discontinued due to IRR or CRS.

Neurologic AEs were transient with none requiring treatment discontinuation. &ldquo;We did not see any grade 4 or above adverse neurologic events,&rdquo; he said. &ldquo;The vast majority of neurologic AEs were grade 1 and 2.&rdquo;

Six patients discontinued the study drug due to treatment-related AEs: 1 for grade 1 cytomegalovirus infection, 1 for grade 3 hemolysis, 1 for grade 3 fatigue, 2 for grade 3 pneumonia, and 1 for grade 3 toxoplasmosis. Two patients discontinued due to AEs unrelated to treatment. Infections/infestations were reported in 50% of patients; only 20% were grade 3/4 in severity with 2 deaths.

Fifteen patients died during the study, most often for progressive disease (n = 10; 1 with grade 5 multiorgan failure and 1 with grade 5 acute renal failure). Other causes of death were gastric perforation, cardiac arrest, lung infection, and pneumonia (1 each); 1 patient died of fungal pneumonia 7 months after discontinuing treatment.

After the data cutoff, a patient treated in the dose-expansion phase with MCL blastoid variant with bone marrow involvement and bulky disease developed CRS and died of tumor lysis syndrome. &ldquo;At present, we halted enrollment in the expansion cohorts while a safety amendment is being put together,&rdquo; he said.

The dose-escalation portion of the phase I trial is complete and expansion cohorts are expected to be re-opened. A global, multi-arm pivotal trial is under way.

Reference:

Bannerji R, Allan JN, Arnason JE, et al. Clinical activity of REGN1979, a bispecific human, anti-CD20 x anti-CD3 antibody, in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Blood. 2019;134(suppl 1;abstr 762) doi: 10.1182/blood-2019-122451.

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